CALL FOR PAPERS Integrative and Translational Physiology: Inflammation and Immunity in Organ System Physiology CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis

Quick ML, Mukherjee S, Rudick CN, Done JD, Schaeffer AJ, Thumbikat P. CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis. Am J Physiol Regul Integr Comp Physiol 303: R580–R589, 2012. First published July 18, 2012; doi:10.1152/ajpregu.00240.2012.—Experimental autoimmune prostatitis (EAP) is a murine model of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in men, a syndrome characterized by chronic pelvic pain. We have demonstrated that chemokine ligands CCL2 and CCL3 are biomarkers that correlate with pelvic pain symptoms. We postulated that CCL2 and CCL3 play a functional role in CPPS and therefore examined their expression in EAP. Upon examination of the prostate 5 days after induction of EAP, CCL2 mRNA was elevated 2to 3-fold, CCL8 by 15-fold, CCL12 by 12to 13-fold, and CXCL9 by 2to 4-fold compared with control mice. At 10 days the major chemokines were CXCL13 and CXCL2; at 20 days CCL2 (1to 2-fold), CCL3 (2to 3-fold) and CCL11 (2to 3-fold); and at 30 days, CCL12 (20to 35-fold) and smaller increases in CCL2, CCL3, and XCL1. Chemokine elevations were accompanied by increases in mast cells and B cells at 5 days, monocytes and neutrophils at day 10, CD4 T cells at day 20, and CD4 and CD8 T cells at day 30. Anti-CCL2 and anti-CCL3 neutralizing antibodies administered at EAP onset attenuated pelvic pain development, but only anti-CCL2 antibodies were effective therapeutically. CCL2and its cognate receptor CCR2-deficient mice were completely protected from development of pain symptoms but assumed susceptibility after reconstitution with wild-type bone marrow. CCL3-deficient mice showed resistance to the maintenance of pelvic pain while CCR5-deficient mice did not show any lessening of pelvic pain severity. These results suggest that the CCL2-CCR2 axis and CCL3 are important mediators of chronic pelvic pain in EAP.